Memory dysfunction and associated abnormalities in prefrontal-hippocampal (PFC-HIPP) circuitry are key vulnerabilities in schizophrenia (SZ). This CIDAR application focuses on the roles of gamma aminobutyric acid (GABA), glutamate (GLU) and brain-derived neurotrophic factor (BDNF) in explaining SZ illness progression, domains associated with memory dysfunction and PFC-HIPP circuitry. We have demonstrated significant sex differences in this circuitry and in memory dysfunction, with males exhibiting worse deficits and higher risk for severity and illness progression than females. Animal and human studies have identified in these brain regions, the co-localization of estrogen (ER-alpha & -beta) and androgen (AR) receptors and glucocorticoid receptors (GR) with GABA and BDNF, which in part regulate their development and ongoing physiology. This study will test a series of hypotheses to begin to explain the increased risk for illness progression in SZ men versus women. We predict that sex differences in memory dysfunction and illness progression will be, in part, explained by GR, ER & AR-associated signaling pathways in gene expression regulating neurotransmitters (GABA and GLU) and growth factors (such as BDNF) in HIPP and PFC. In the proposed study, we will characterize sex differences in the associations between deficits in brain activity in PFC-HIPP circuitry in response to a memory task conducted using functional magnetic resonance imaging, structural abnormalities in PFC-HIPP circuitry, and neuroendocrine dysfunction associated with these brain deficits in SZ compared with normal controls. Further, we will relate abnormalities in GABA genes, BDNF, ER, AR and GR genes to these sex differences in brain abnormalities and hormonal dysregulation and begin to validate associationsbetween GR, ER and AR mRNA, BDNF and GABA in HIPP and PFC in postmortem tissue in SZ and normal control men and women. The CIDAR consortium will allow for an adequate number of prodromal, first episode, and chronic cases of SZ and controls (n=394) and the use of functional and structural magnetic imaging, hormonal evaluations, molecular genetics, and postmortem tissue experiments to test our hypotheses regarding sex differences in illness progression in SZ. An investigation of the trajectory of sex differences at different levels of illness progression is important in that it may provide insights into the timing of potential differential hormonal interventions for men and women with SZ.